Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death

Dan Weng, Robyn Marty-Roix, Sandhya Ganesan, Megan K. Proulx, Gregory I. Vladimer, William J. Kaiser, Edward S. Mocarski, Kimberly Pouliot, Francis Ka Ming Chan, Michelle A. Kelliher, Phillip A. Harris, John Bertin, Peter J. Gough, Dmitry M. Shayakhmetov, Jon D. Goguen, Katherine A. Fitzgerald, Neal Silverman, Egil Lien

Research output: Contribution to journalArticlepeer-review

179 Scopus citations


A number of pathogens cause host cell death upon infection, and Yersinia pestis, infamous for its role in large pandemics such as the "Black Death" in medieval Europe, induces considerable cytotoxicity. The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effector Yersinia outer protein J (YopJ), is minimally affected by the absence of caspase-1, caspase- 11, Fas ligand, and TNF. Caspase-8 is known to mediate apoptotic death in response to infection with several viruses and to regulate programmed necrosis (necroptosis), but its role in bacterially induced cell death is poorly understood. Here we provide genetic evidence for a receptor-interacting protein (RIP) kinase- caspase-8-dependent macrophage apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain- containing adapter-inducing interferon-β (TLR4-TRIF). Interestingly, macrophages lacking either RIP1, or caspase-8 and RIP3, also had reduced infection-induced production of IL-1β, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-κB; and greatly compromised caspase-1 processing. Cleavage of the proform of caspase-1 is associated with triggering inflammasome activity, which leads to the maturation of IL-1β and IL-18, cytokines important to host responses against Y. pestis and many other infectious agents. Our results identify a RIP1-caspase-8/RIP3-dependent caspase- 1 activation pathway after Y. pestis challenge. Mice defective in caspase-8 and RIP3 were also highly susceptible to infection and displayed reduced proinflammatory cytokines and myeloid cell death. We propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-κB and inflammasome activation, and host resistance after Y. pestis infection.

Original languageEnglish (US)
Pages (from-to)7391-7396
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - May 20 2014

ASJC Scopus subject areas

  • General


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